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Nucleic Acids Research Sep 2016The equilibrium of stacked and unstacked base pairs is of central importance for all nucleic acid structure formation processes. The stacking equilibrium is influenced...
The equilibrium of stacked and unstacked base pairs is of central importance for all nucleic acid structure formation processes. The stacking equilibrium is influenced by intramolecular interactions between nucleosides but also by interactions with the solvent. Realistic simulations on nucleic acid structure formation and flexibility require an accurate description of the stacking geometry and stability and its sequence dependence. Free energy simulations have been conducted on a series of double stranded DNA molecules with a central strand break (nick) in one strand. The change in free energy upon unstacking was calculated for all ten possible base pair steps using umbrella sampling along a center-of-mass separation coordinate and including a comparison of different water models. Comparison to experimental studies indicates qualitative agreement of the stability order but a general overestimation of base pair stacking interactions in the simulations. A significant dependence of calculated nucleobase stacking free energies on the employed water model was observed with the tendency of stacking free energies being more accurately reproduced by more complex water models. The simulation studies also suggest a mechanism of stacking/unstacking that involves significant motions perpendicular to the reaction coordinate and indicate that the equilibrium nicked base pair step may slightly differ from regular B-DNA geometry in a sequence-dependent manner.
Topics: Base Pairing; DNA; DNA, B-Form; Thermodynamics
PubMed: 27407106
DOI: 10.1093/nar/gkw607 -
Analytical Sciences : the International... Mar 2021Anisotropic gold nanoparticles have attracted great interest due to their unique physicochemical properties derived from the shape anisotropy. Manipulation of their... (Review)
Review
Anisotropic gold nanoparticles have attracted great interest due to their unique physicochemical properties derived from the shape anisotropy. Manipulation of their interfacial interactions, and thereby the assembling behaviors are often requisite in their applications ranging from optical sensing and diagnosis to self-assembly. Recently, the control of interfacial force based on base pair stacking of DNA terminals have offered a new avenue to surface engineering of nanostructures. In this review, we focus on the DNA base stacking-induced assembly of anisotropic gold nanoparticles, such as nanorods and nanotriangles. The fundamental aspects of anisotropic gold nanoparticles are provided, including the mechanism of the anisotropic growth, the properties arising from the anisotropic shape, and the construction of DNA-grafted anisotropic gold nanoparticles. Then, the advanced applications of their functional assemblies in biosensing and ordered assembly are summarized, followed by a comparison with gold nanospheres. Finally, conclusions and the direction of outlooks are given including future challenges and opportunities in this field.
Topics: Anisotropy; Base Pairing; Biosensing Techniques; DNA; Gold; Metal Nanoparticles
PubMed: 33071270
DOI: 10.2116/analsci.20SCR02 -
Chemical & Pharmaceutical Bulletin 2018In this review, we have summarized the research effort into the development of unnatural base pairs beyond standard Watson-Crick (WC) base pairs for synthetic biology.... (Review)
Review
In this review, we have summarized the research effort into the development of unnatural base pairs beyond standard Watson-Crick (WC) base pairs for synthetic biology. Prior to introducing our research results, we present investigations by four outstanding groups in the field. Their research results demonstrate the importance of shape complementarity and stacking ability as well as hydrogen-bonding (H-bonding) patterns for unnatural base pairs. On the basis of this research background, we developed unnatural base pairs consisting of imidazo[5',4':4.5]pyrido[2,3-d]pyrimidines and 1,8-naphthyridines, i.e., Im : Na pairs. Since Im bases are recognized as ring-expanded purines and Na bases are recognized as ring-expanded pyrimidines, Im : Na pairs are expected to satisfy the criteria of shape complementarity and enhanced stacking ability. In addition, these pairs have four non-canonical H-bonds. Because of these preferable properties, ImN : NaO, one of the Im : Na pairs, is recognized as a complementary base pair in not only single nucleotide insertion, but also the PCR.
Topics: Base Pairing; Hydrogen Bonding; Naphthyridines; Physical Phenomena; Purines; Pyrimidines; Synthetic Biology
PubMed: 29386463
DOI: 10.1248/cpb.c17-00685 -
Molecules (Basel, Switzerland) Oct 2012Strand separation is a fundamental molecular process essential for the reading of the genetic information during DNA replication, transcription and recombination.... (Review)
Review
Strand separation is a fundamental molecular process essential for the reading of the genetic information during DNA replication, transcription and recombination. However, DNA melting in physiological conditions in which the double helix is expected to be stable represents a challenging problem. Current models propose that negative supercoiling destabilizes the double helix and promotes the spontaneous, sequence-dependent DNA melting. The present review examines an alternative view and reveals how DNA compaction may trigger the sequence dependent opening of the base pairs. This analysis shows that in DNA crystals, tight DNA-DNA interactions destabilize the double helices at various degrees, from the alteration of the base-stacking to the opening of the base-pairs. The electrostatic repulsion generated by the DNA close approach of the negatively charged sugar phosphate backbones may therefore provide a potential source of the energy required for DNA melting. These observations suggest a new molecular mechanism for the initial steps of strand separation in which the coupling of the DNA tertiary and secondary interactions both actively triggers the base pair opening and stabilizes the intermediate states during the melting pathway.
Topics: Base Pairing; DNA; DNA Replication; Models, Biological; Nucleic Acid Conformation; Nucleic Acid Denaturation
PubMed: 23060287
DOI: 10.3390/molecules171011947 -
Metallomics : Integrated Biometal... Apr 2021Artificial metal base pairs have become increasingly important in nucleic acids chemistry due to their high thermal stability, water solubility, orthogonality to natural... (Review)
Review
Artificial metal base pairs have become increasingly important in nucleic acids chemistry due to their high thermal stability, water solubility, orthogonality to natural base pairs, and low cost of production. These interesting properties combined with ease of chemical and enzymatic synthesis have prompted their use in several practical applications, including the construction of nanomolecular devices, ions sensors, and metal nanowires. Chemical synthesis of metal base pairs is highly efficient and enables the rapid screening of novel metal base pair candidates. However, chemical synthesis is limited to rather short oligonucleotides and requires rather important synthetic efforts. Herein, we discuss recent progress made for the enzymatic construction of metal base pairs that can alleviate some of these limitations. First, we highlight the possibility of generating metal base pairs using canonical nucleotides and then describe how modified nucleotides can be used in this context. We also provide a description of the main analytical techniques used for the analysis of the nature and the formation of metal base pairs together with relevant examples of their applications.
Topics: Base Pairing; Coordination Complexes; DNA-Directed DNA Polymerase; Metals; Nucleic Acids
PubMed: 33791776
DOI: 10.1093/mtomcs/mfab016 -
BMC Bioinformatics Dec 2019A pairings of nucleotide sequences. Given this forbidding free-energy landscape, mechanisms have evolved that contribute to a directed and efficient folding process,...
BACKGROUND
A pairings of nucleotide sequences. Given this forbidding free-energy landscape, mechanisms have evolved that contribute to a directed and efficient folding process, including catalytic proteins and error-detecting chaperones. Among structural RNA molecules we make a distinction between "bound" molecules, which are active as part of ribonucleoprotein (RNP) complexes, and "unbound," with physiological functions performed without necessarily being bound in RNP complexes. We hypothesized that unbound molecules, lacking the partnering structure of a protein, would be more vulnerable than bound molecules to kinetic traps that compete with native stem structures. We defined an "ambiguity index"-a normalized function of the primary and secondary structure of an individual molecule that measures the number of kinetic traps available to nucleotide sequences that are paired in the native structure, presuming that unbound molecules would have lower indexes. The ambiguity index depends on the purported secondary structure, and was computed under both the comparative ("gold standard") and an equilibrium-based prediction which approximates the minimum free energy (MFE) structure. Arguing that kinetically accessible metastable structures might be more biologically relevant than thermodynamic equilibrium structures, we also hypothesized that MFE-derived ambiguities would be less effective in separating bound and unbound molecules.
RESULTS
We have introduced an intuitive and easily computed function of primary and secondary structures that measures the availability of complementary sequences that could disrupt the formation of native stems on a given molecule-an ambiguity index. Using comparative secondary structures, the ambiguity index is systematically smaller among unbound than bound molecules, as expected. Furthermore, the effect is lost when the presumably more accurate comparative structure is replaced instead by the MFE structure.
CONCLUSIONS
A statistical analysis of the relationship between the primary and secondary structures of non-coding RNA molecules suggests that stem-disrupting kinetic traps are substantially less prevalent in molecules not participating in RNP complexes. In that this distinction is apparent under the comparative but not the MFE secondary structure, the results highlight a possible deficiency in structure predictions when based upon assumptions of thermodynamic equilibrium.
Topics: Base Pairing; Base Sequence; Calibration; Kinetics; Nucleic Acid Conformation; RNA; RNA Folding; ROC Curve; Thermodynamics
PubMed: 31830902
DOI: 10.1186/s12859-019-3303-6 -
Bioinformatics (Oxford, England) Nov 2023The two strands of the DNA double helix locally and spontaneously separate and recombine in living cells due to the inherent thermal DNA motion. This dynamics results in...
MOTIVATION
The two strands of the DNA double helix locally and spontaneously separate and recombine in living cells due to the inherent thermal DNA motion. This dynamics results in transient openings in the double helix and is referred to as "DNA breathing" or "DNA bubbles." The propensity to form local transient openings is important in a wide range of biological processes, such as transcription, replication, and transcription factors binding. However, the modeling and computer simulation of these phenomena, have remained a challenge due to the complex interplay of numerous factors, such as, temperature, salt content, DNA sequence, hydrogen bonding, base stacking, and others.
RESULTS
We present pyDNA-EPBD, a parallel software implementation of the Extended Peyrard-Bishop-Dauxois (EPBD) nonlinear DNA model that allows us to describe some features of DNA dynamics in detail. The pyDNA-EPBD generates genomic scale profiles of average base-pair openings, base flipping probability, DNA bubble probability, and calculations of the characteristically dynamic length indicating the number of base pairs statistically significantly affected by a single point mutation using the Markov Chain Monte Carlo algorithm.
AVAILABILITY AND IMPLEMENTATION
pyDNA-EPBD is supported across most operating systems and is freely available at https://github.com/lanl/pyDNA_EPBD. Extensive documentation can be found at https://lanl.github.io/pyDNA_EPBD/.
Topics: Computer Simulation; Models, Chemical; DNA; Software; Base Pairing; Nucleic Acid Conformation
PubMed: 37991847
DOI: 10.1093/bioinformatics/btad699 -
Current Issues in Molecular Biology Jan 2000An efficient, PCR based method for the selective amplification of DNA target sequences that differs by a single base pair is described. The method utilises the high... (Review)
Review
An efficient, PCR based method for the selective amplification of DNA target sequences that differs by a single base pair is described. The method utilises the high affinity and specificity of PNA for their complementary nucleic acids and that PNA cannot function as primers for DNA polymerases.
Topics: Alleles; Base Pairing; Binding, Competitive; DNA Primers; Nucleic Acid Denaturation; Nucleic Acid Renaturation; Point Mutation; Polymerase Chain Reaction
PubMed: 11464917
DOI: No ID Found -
Current Protocols in Nucleic Acid... Dec 2014Base pairing in nucleic acids plays a crucial role in their structure and function. Differences in the base-pair opening and closing kinetics of individual... (Review)
Review
Base pairing in nucleic acids plays a crucial role in their structure and function. Differences in the base-pair opening and closing kinetics of individual double-stranded DNA sequences or between chemically modified base pairs provide insight into the recognition of these base pairs by DNA processing enzymes. This unit describes how to quantify the kinetics for localized base pairs by observing changes in the imino proton signals by nuclear magnetic resonance spectroscopy. The determination of all relevant parameters using state-of-the art techniques and NMR instrumentation, including cryoprobes, is discussed.
Topics: Base Pairing; DNA; Kinetics; Magnetic Resonance Spectroscopy
PubMed: 25501592
DOI: 10.1002/0471142700.nc0720s59 -
Bioinformatics (Oxford, England) Oct 2022Machine learning models for predicting cell-type-specific transcription factor (TF) binding sites have become increasingly more accurate thanks to the increased...
MOTIVATION
Machine learning models for predicting cell-type-specific transcription factor (TF) binding sites have become increasingly more accurate thanks to the increased availability of next-generation sequencing data and more standardized model evaluation criteria. However, knowledge transfer from data-rich to data-limited TFs and cell types remains crucial for improving TF binding prediction models because available binding labels are highly skewed towards a small collection of TFs and cell types. Transfer prediction of TF binding sites can potentially benefit from a multitask learning approach; however, existing methods typically use shallow single-task models to generate low-resolution predictions. Here, we propose NetTIME, a multitask learning framework for predicting cell-type-specific TF binding sites with base-pair resolution.
RESULTS
We show that the multitask learning strategy for TF binding prediction is more efficient than the single-task approach due to the increased data availability. NetTIME trains high-dimensional embedding vectors to distinguish TF and cell-type identities. We show that this approach is critical for the success of the multitask learning strategy and allows our model to make accurate transfer predictions within and beyond the training panels of TFs and cell types. We additionally train a linear-chain conditional random field (CRF) to classify binding predictions and show that this CRF eliminates the need for setting a probability threshold and reduces classification noise. We compare our method's predictive performance with two state-of-the-art methods, Catchitt and Leopard, and show that our method outperforms previous methods under both supervised and transfer learning settings.
AVAILABILITY AND IMPLEMENTATION
NetTIME is freely available at https://github.com/ryi06/NetTIME and the code is also archived at https://doi.org/10.5281/zenodo.6994897.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Base Pairing; Binding Sites; High-Throughput Nucleotide Sequencing; Protein Binding; Transcription Factors
PubMed: 35997560
DOI: 10.1093/bioinformatics/btac569